Robert H. Fillingame
 |
Professor & Chair
Office: (608) 262-1439 |
Education
- BS 1968, Washington State University;
- PhD 1973, University of Washington, Seattle;
- Postdoctoral, 1973-75, Harvard Medical School (E.P. Kennedy).
Honors & Awards
- Medical Alumni Named Professorship, 1988;
- NIH Merit Award, 1994;
- WARF Mid-Career Faculty Researcher Award, 1998.
Research Interests
My research focuses on the molecular mechanism of ATP synthesis during oxidative phosphorylation. ATP synthesis is driven by a trans membrane proton gradient generated by the electron transport system. The enzyme catalyzing ATP synthesis is biologically unique in using the electrochemical energy of the proton gradient to drive the rotation of a molecular motor which in turn drives ATP synthesis. The ATP synthase has been termed the "world's smallest rotary motor". The process works as follows. Proton transport through the Fo membrane sector of the enzyme is coupled with the rotation of a molecular rotor composed of multiple c subunits. The c oligomeric rotor in turn drives ATP synthesis via the rotation of two attached subunits (gamma and epsilon) which cycle between circularly arranged multiple catalytic sites in the extramembranous F1 sector of the enzyme. In the complete process of ATP synthesis the electrochemical energy of the proton gradient is converted into mechanical energy and, via structural/mechanical changes in the catalytic sites, ultimately into the chemical energy of ATP. Our long term goal is to elucidate the structure and molecular mechanism of this fascinating machine.
Publications of Note
Jiang, W., Hermolin, J., & Fillingame, R. H. 2001. The Preferred Stoichiometry of c Subunits in the Rotary Motor Sector of Escherichia coli ATP Synthase Is Ten. Proc. Natl. Acad. Sci. USA 98:4966-4971.
Valiyaveetil, F. I., Hermolin, J., and Fillingame. R. H. 2002. pH Dependent Inactivation of Solubilized F1Fo ATP Synthase by Dicyclohexylcarbodiimide: pKa of Detergent Unmasked Aspartyl 61 in Escherichia coli Subunit c. Biochim. Biophys. Acta, 1553:296-301.
Dmitriev, O. Y., Abildgaard, F., Markley, J. L., and Fillingame, R. H. 2002. Structure of Ala24/Asp61?Asp24/Asn61 Substituted Subunit c of Escherichia coli ATP Synthase: Implications for the Mechanism of Proton Transport and Rotary Movement in the Fo Complex. Biochemistry 41:5537- 5547.
Fillingame, R. H., and Dmitriev, O. Y. 2002. Structural Model of the Transmembrane Fo Rotary Sector of H+-Transporting ATP Synthase Derived by Solution NMR and Intersubunit Cross-Linking In Situ. Biochim. Biophys. Acta 1565: 232-245.
Fillingame, R. H., Angevine, C. M., and Dmitriev, O. Y. 2002. Coupling Proton Movements to c-Ring Rotation in F1Fo ATP Synthase: Aqueous Access Channels and Helix Rotations at the a-c Interface. Biochim. Biophys. Acta 1555: 29-36.
Angevine, C. M., and Fillingame, R. H. 2003. Aqueous Access Channels in Subunit a of Rotary ATP Synthase. J. Biol. Chem. 278:6066-6074.
Angevine, C. M., Herold, K. A. G., and Fillingame, R. H. 2003. Aqueous Access Pathways in Subunit a of Rotary ATP Synthase Extend to Both Sides of the Membrane. Proc. Natl. Acad. Sci. USA 100:13179- 13183.
Fillingame, R. H., Angevine, C. M., and Dmitriev, O. Y. 2003. Mechanics of Coupling Proton Movements to c-Ring Rotation in ATP Synthase. FEBS Lett. 555:29-34.
Dmitriev, O. Y., Altendorf, K., and Fillingame, R. H. 2004. Subunit a of the Escherichi a coli ATP Synthase: Reconstitution and High Resolution NMR with Protein Purified in a Mixed Polarity Solvent. FEBS Lett. 556:35-38.
Aksimentiev, A., Balabin, I. A., Fillingame, R. H., and Schulten, K. 2004. Insights into the Molecular Mechanism of Rotation in the Fo Sector of ATP Synthase. Biophys. J. 86:1332-1344.
Schwem, B. E. and Fillingame, R. H. 2006. Cross-Linking Between Helices Within Subunit a of Escherichia coli ATP Synthase Defines the Transmembrane Packing of a Four Helix Bundle. J. Biol. Chem. 281: 37861-37867.
Angevine, C. M., Herold, K. A. G., Vincent, O.D. and Fillingame, R. H. 2007. Aqueous Access Pathways in ATP Synthase Subunit a: Reactivity of Cysteine Substituted into Transmembrane Helices 1, 3 and 5. J. Biol. Chem. 282: 9001-9007.
Vincent, O. D., Schwem, B. E., Steed, P. R., Jiang, W., and Fillingame, R. H. 2007. Fluidity of Structure and Swiveling of Helices in the Subunit c Ring of Escherichia coli ATP Synthase As Revealed by Cys-Cys Cross-Linking. J. Biol. Chem. 282: 33788-33794.
Dmitriev, O. Y., and Fillingame, R. H. 2007. The Rigid Connecting Loop Stabilizes Hairpin Folding of the Two Helices of the ATP Synthase Subunit c. Protein Science 16: 2118-2122.
Dmitriev, O. Y., Friedman, K., Hermolin, J., and Fillingame, R. H. 2008. Interaction of Transmembrane Helices in ATP Synthase Subunit a in Solution as Revealed by Spin-Label Difference NMR. Biochim. Biophys. Acta 1777: 227-237.
Steed, P. R., and Fillingame, R. H. 2008. Subunit a Facilitates Aqueous Access to a Membrane-Embedded Region of Subunit c in Escherichia coli ATP Synthase. J. Biol. Chem. 283: 12365-12372.
Moore, K. J., Angevine, C. M., Vincent, O. D., and Fillingame, R. H. 2008. The Cytoplasmic Loops of Subunit a of Escherichia coli ATP Synthase May Participate in the Proton Translocating Mechanism. J. Biol. Chem. 283: 13044-13052.
Moore, K. J., and Fillingame, R. H. 2008. Structural Interactions Between Transmembrane Helices 4 and 5 of Subunit a and the Subunit c Ring of Escherichia coli ATP Synthase. J. Biol. Chem. 283: 31726-31735.
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University
of Wisconsin - Department
of Biomolecular Chemistry
First published: 01/01/05 Last updated:19 March 2009 Email Biomolecular Chemistry
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